Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results

Bournemouth University, Bournemouth, England, United Kingdom
British Journal of Haematology (Impact Factor: 4.71). 04/2003; 120(6):944-52. DOI: 10.1046/j.1365-2141.2003.04172.x
Source: PubMed


The cytogenetic picture in multiple myeloma (MM) is highly complex, from which non-random numerical and structural chromosomal changes have been identified. Specifically, translocations involving the immunoglobulin heavy chain gene (IGH) at 14q32 and either monosomy or deletions of chromosome 13 have been reported in a significant number of patients from both cytogenetic and interphase fluorescence in situ hybridization (FISH) studies. Importantly, these abnormalities of chromosome 13 have recently been associated with a poor prognosis. In view of the highly complex nature of the karyotypes in MM patients, interphase FISH results may be difficult to interpret. In this study, cytogenetics and/or interphase FISH were carried out on bone marrow samples or purified plasma cells from 37 MM patients. Abnormal karyotypes, characterized by multiplex FISH (M-FISH) were found in 11 patients, all of which were highly complex. Interphase FISH revealed translocations involving the IGH locus in 16 (43%) patients. The IGH/cyclin D1 (CCND1) gene fusion characteristic of the translocation, t(11;14)(q13;q32), was seen in 12 (32%) of these patients and other rearrangements of IGH in four (11%) patients. Fourteen patients had additional copies of chromosome 11. Twenty patients (54%) had 13q14 deletions, 10 of whom also had t(11;14) or another IGH translocation. By comparing cytogenetic and FISH results, this study has revealed that significant chromosomal abnormalities might be hidden within highly complex karyotypes. Therefore, extreme caution is required in the interpretation of interphase FISH results in MM, particularly in relation to certain abnormalities, such as 13q14 deletions, which have an impact on prognosis.

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Available from: Atul Mehta, Sep 15, 2014
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    • "Being the most common abnormality in CLL [9, 10], deletions at 13q14.3 are associated with the longest survival. Rearrangements and/or deletions in the region of 13q14.3 are found in many other types of hematopoietic malignancies, including 38% of mantle cell lymphomas [11] and approximately 54% of multiple myelomas (MM) as detected by fluorescence in situ hybridization [12, 13]. In the majority of these non-CLL cases, 13q14 deletions are associated with a poor chemotherapy response profile. "
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    ABSTRACT: Deletion of 13q14.3 and a candidate gene KCNRG (potassium channel regulating gene) is the most frequent chromosomal abnormality in B-cell chronic lymphocytic leukemia and is a common finding in multiple myeloma (MM). KCNRG protein may interfere with the normal assembly of the K+ channel proteins causing the suppression of Kv currents. We aimed to examine possible role of KCNRG haploinsufficiency in chronic lymphocytic leukemia (CLL) and MM cells. We performed detailed genomic analysis of the KCNRG locus; studied effects of the stable overexpression of KCNRG isoforms in RPMI-8226, HL-60, and LnCaP cells; and evaluated relative expression of its transcripts in various human lymphomas. Three MM cell lines and 35 CLL PBL samples were screened for KCNRG mutations. KCNRG exerts growth suppressive and pro-apoptotic effects in HL-60, LnCaP, and RPMI-8226 cells. Direct sequencing of KCNRG exons revealed point mutation delT in RPMI-8226 cell line. Levels of major isoform of KCNRG mRNA are lower in DLBL lymphomas compared to normal PBL samples, while levels of its minor mRNA are decreased across the broad range of the lymphoma types. The haploinsufficiency of KCNRG might be relevant to the progression of CLL and MM at least in a subset of patients. Electronic supplementary material The online version of this article (doi:10.1007/s13277-009-0005-0) contains supplementary material, which is available to authorized users.
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    • "abnormal abnormal 2 8 No 45,X,ÀY[5]/46,XY[25] normal abnormal 3 5 No 45,X,ÀY[10]/46,XY[20] normal abnormal 4 10 Yes 46,XY[30] normal abnormal 5 15 Yes 46,XY[30] normal abnormal 6 69 No 53,XX,þdel(1)(p13),þ3,del(4)(q12q32), þ5,þ7,À8,þ9,þ11,þ15,þ15[5]/53,XX, þ3,þ5,þ7,À8,þadd(9)(q34),þ11,þ15, þ19,þmar[3]/46,XX[12] abnormal abnormal 7 1 5 e20 No 46,XY[30] normal abnormal 8 10 Yes 46,XY[30] normal abnormal 9 sheets Yes 46,XY[20] ND abnormal 10 10 No 46,XY[20] normal abnormal 11 7 No 45,X,ÀY[14]/46,XY[16] abnormal abnormal 12 30 No 46,XY[30] normal abnormal 13 50 Yes 46,XY[20] abnormal abnormal 14 10 No 46,XY[30] abnormal abnormal 15 15 No 46,XY[20] normal abnormal 16 60 Yes 50,XY,þ3,þ5,þ9,þ15,þ15,þ19,À20, À21[1]/46,XY[19] abnormal abnormal 17 20 Yes 45,X,ÀY[17]/46,XY[3] normal abnormal 18 5 Yes 46,XX[30] abnormal abnormal 19 10 Yes ND ND abnormal 20 50 No, s/p chemo 46,XX[20] normal abnormal 21 1 Yes 45,X,ÀY[18]/46,XY[12] normal abnormal 22 43 Yes 46,XX[30] abnormal abnormal 23 5 No 46,XY[20] normal abnormal 24 10e20 No, s/p chemo 46,XY[20] abnormal abnormal 25 3e5 No, s/p autologous transplant 46,XY[20] normal abnormal 26 23 Yes 46,XY[30] abnormal abnormal 27 2e10 Yes 46,XY[30] "
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    ABSTRACT: Historically, cytogenetic studies of plasma cell neoplasms have been hampered by the fact that terminally differentiated plasma cells do not proliferate well in vitro. Although the use of interphase FISH (iFISH) has greatly improved the ability to detect cytogenetic abnormalities, cases with low numbers of neoplastic cells often do not demonstrate abnormalities. Using a four-assay, nine-probe iFISH panel, we compared the abnormality detection rate for overnight unstimulated bone marrow cultures (ONC) to that for plasma-cell enriched fractions obtained with use of CD138-coated immunomagnetic beads (PCE). In the ONC, an abnormality was detected in 11 of 29 cases (38%); in the PCE, an abnormality was detected in 30 of 33 cases (91%). For 28 cases in which iFISH results from ONC were compared directly with PCE samples, the overall abnormality rate was 36% for ONC and 89% for PCE (P < 0.01). The conventional GTG-banded chromosome analysis revealed only 2 of 34 cases with an abnormal karyotype (6%); both cases were hyperdiploid. We conclude that the plasma cell enrichment step for iFISH should be incorporated into the routine cytogenetic work-up for all patients with plasma cell neoplasms.
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    • "These methods have proved particularly useful in the analyses of complex karyotypes (Ashman et al., 2002; Barbouti et al., 2002; Cohen et al., 2002; Tchinda et al., 2003). Although FISH undoubtedly increases the sensitivity, it should be stressed that it cannot replace chromosome banding; it should be considered a supplement (Harrison et al., 2003). Figure 4. Examples of different FISH probes (from left to right): locus specific, centromeric, subtelomeric, partial chromosome painting, and whole chromosome painting. "

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